Tacrolimus liver transplantation

Haddad EM, McAlister VC, Renouf E et al (2006) Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev (4) CD005161... 

The expression level of intestinal MDR1 mRNA has been utilized to the personalized immunosuppressant therapy with tacrolimus in cases of living-donor liver transplantation (LDLT) [84], Tacrolimus shows wide... 

S. Masuda, M. Goto, M. Okuda, Y. Ogura, F. Oike, T. Kiuchi, K. Tanaka, and K. Inui. Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients. Transplant Proc 37 1728-1729 (2005). 

Liver transplant recipients - Safety and efficacy in liver transplant recipients are unknown. If entecavir treatment is necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function (eg, cyclosporine, tacrolimus), renal function must be carefully monitored before and during treatment with entecavir. 

The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein and has a high level of association with erythrocytes. It is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P450 system (CYP3A). The disposition of tacrolimus from whole blood was biphasic with a terminal elimination half-life of 11.7 hours in liver transplant patients. 

Nephrotoxicity Tacrolimus can cause nephrotoxicity, particularly when used in high doses. Nephrotoxicity has been noted in approximately 52% of kidney transplantation patients and in 33% to 40% of liver transplantation patients receiving the drug. 

Renal/Hepatic function impairment The use of tacrolimus in liver transplant recipients experiencing posttransplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels of tacrolimus. 

Coadministered grapefruit juice has been reported to increase tacrolimus blood trough concentrations in liver transplant patients. 

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information needed for the follow-up of the patient. Liver transplantation-excess mortality, graft loss, and hepatic artery thrombosis (HAT) The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. 

In this and another study in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death. 

The investigators measured messenger ribonucleic acid (mRNA) expression levels of MDRl and CYP3A4 in mucosal cells of the upper jejunum collected during living-donor liver transplantation in 48 recipients. Tacrolimus was initiated at an oral dose of 0.075 mg/kg every 12 hours and adjusted on the basis of trough levels in whole blood. 

Busuttil RW, Lake JR. 2004. Role of tacrolimus in the evolution of liver transplantation. Transplantation. 77 S44-S51. 

Hypertriglyceridemia due to sirolimus often does not respond to dosage reduction or hypolipidemic drugs. After liver transplantation (n — 6), significant hyperlipidemia improved after withdrawal of sirolimus (1070). The incidence of sirolimus-associated hyperlipidemia is up to 44%. After liver transplantation, there was hypercholesterolemia in 15% and hypertriglyceridemia in 10% of recipients. Sirolimus in combination with tacrolimus... 

The risk of post-transplant diabetes mellitus is greater with tacrolimus than with ciclosporin, but this was mostly true in black patients and during the initial months after transplantation (1084). In one study, insulin sensitivity, alpha and beta cell function, and beta cell reserve were studied in 14 hepatitis C-positive patients with liver transplants, who took tacrolimus or ciclosporin maintenance for 1 year (1085). The patients were matched for low prednisolone dosage (1.1 mg/day versus 1.3 mg/day), body mass index, lean body mass, and sex, and compared with eight controls. Insulin sensitivity and insulin secretory reserve were significantly different from controls, but there was no significant difference between ciclosporin and tacrolimus. 

The incidence, mechanism, and risk factors of tacroli-mus-associated diabetes mellitus are still debated. In 58 patients investigated 1-3 years after liver transplantation there was a significantly higher incidence of diabetes mellitus with tacrolimus (n = 32) compared with ciclosporin (n = 26) (1086). Newly-diagnosed diabetes... 

Hyperuricemia has been reported in association with ciclosporin and tacrolimus. In two cases there was a direct association between tacrolimus and gout after liver transplantation (1103). 

Jain A, Kashyap R, Marsh W, Rohal S, Khanna A, Fung JJ. Reasons for long-term use of steroid in primary adult liver transplantation under tacrolimus. Transplantation 2001 71(8) 1102-6. 

Gerster JC, Dudler M, Halkic N, Gillet M. Gout in liver transplant patients receiving tacrolimus. Ann Rheum Dis 2004 63(7) 894-5. 

Yamauchi A, Ieiri I, Kataoka Y, Tanabe M, Nishizaki T, Oishi R, Higuchi S, Otsubo K, Sugimachi K. Neurotoxicity induced by tacrolimus after liver transplantation relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002 74 571-578. 

A 5 year old girl developed speech arrest, agitation, tremor, ataxia, and deviation of downward gaze 13 days after liver transplantation (610). The tacrolimus trough concentration was 44 ng/ml. Three days after dosage reduction, she could say a few words and her extra-ocular movements returned to normal. Four months later, she continued to have reduced fluency, dysarthria, and ataxia. One year later, the reduced fluency and mild ataxia persisted. 

Sokol DK, Molleston JP, Filo RS, Van Valer J, Edwards-Brown M. Tacrolimus (FK506)-induced mutism after liver transplant. Pediatr Neurol 2003 28 156-8. 

Jonas, S., Neuhaus, R., Junge, G., Kin, J., Theruvat, T., Langrehr, J.M., Settmacher, U., Neuhaus, P. Primary immunosuppression with tacrolimus after liver transplantation 12-years follow-up. Internal. Immuno-pharm. 2005 5 125-128... 

Pratschke, J., Neuhaus, R., Tullius, S.G., Haller, G.W., Jonas, S., Stein-mueller, T., Bechstein, W.O., Neuhaus, P. Treatment of cyclosporine-related adverse effects by conversion to tacrolimus after liver transplantation. Transplantation 1997 64 938-940... 

Marcos A, Eghtesad B, Fung JJ, Fontes P, Patel K, Devera M, Marsh W, Gayowski T, Demetris AJ, Gray EA, Flynn B, Zeevi A, Murase N, Starzl TE. Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation with particular reference to hepatitis C virus Transplantation 2004 78(7) 966-71. 

A 47-year-old white man with a cadaveric liver transplant took chloramphenicol for a urinary tract infection due to a vancomycin-resistant Enterococcus and inadvertently received 1850 mg qds (roughly twice the maximum recommended dose). On day 4 he had a 12-hour trough tacrolimus concentration of over 60 ng/ml. 

Neurological symptoms were observed in 12-25% of liver-transplant patients and in 29% of bone marrow transplant patients, but severe neurotoxicity occurred only in about 1% (18,19/21). They usually appeared within the first month of treatment, but were sometimes delayed (19). Particular attention should be paid to prompt recognition of severe neurotoxicity, because abnormalities of the white matter can occur. Patients usually improved rapidly after temporary ciclosporin withdrawal or dosage reduction, and tacrolimus has sometimes been used successfully instead (SEDA-21, 383) (18). However, recurrence of seizures and persistent electroencephalographic abnormahties were found in 46 and 70% of pediatric transplant patients respectively who had had ciclosporin acute encephalopathy and seizure syndrome and who were followed-up for 49 months (22). 

A 68-year-old man developed diarrhea, dehydration, and atrial fibrillation 4 months after liver transplantation. He was taking tacrolimus (blood concentration 13 ng/ml) and was given a continuous infusion of diltiazem for 1 day followed by oral therapy. Three days later he became delirious, confused, and agitated, and the blood concentration of tacrolimus was 55 ng/ml. His mental statns gradnally improved after withdrawal of both dmgs. 

Since tacrolimus (FK506) is metabolized by intestinal and hepatic CYP3A4, drugs that inhibit CYP3A4 can reduce the metabolism of tacrolimus and increase tacrolimus blood concentrations (111). The effect of fluconazole on the blood concentrations of tacrolimus have been investigated in eight liver transplant patients in whom prophylactic fluconazole (200 mg/day) was withdrawn because of rises in hepatic transaminases (n = 6), renal dysfunction, or eosinophilia (n = 1 each) (112). Calculated tacrolimus concentrations fell by 13-81% (median 41%) between the fourth and ninth days after withdrawal of fluconazole. Tacrolimus blood concentrations should be carefully monitored and dosages increased as necessary after withdrawal of fluconazole. 

Stegall MD, Wachs ME, Everson G, Steinberg T, Bilir B, Shrestha R, Karrer F, Kam I. Prednisone withdrawal 14 days after liver transplantation with mycophenolate a prospective trial of cyclosporine and tacrolimus. Transplantation 1997 64(12) 1755-60. 

An interaction of nelfinavir with the macrolide immunosuppressant tacrolimus has been reported in a patient co-infected with HIV and hepatitis C virus who had undergone orthotopic liver transplantation (18). The dose of tacrolimus had to be reduced to a 70th of the normal dose to avoid adverse effects. Nelfinavir serum concentrations were not affected by tacrolimus. The authors suggested that this effect had resulted from inhibition of the metabolism of tacrolimus, because both compounds are substrates of CYP3A4. 

Schvarcz R, Rudbeck G, Soderdahl G, Stable L. Interaction between nelfinavir and tacrolimus after orthoptic liver transplantation in a patient coinfected with HIV and hepatitis C virus (HCV). Transplantation 2000 69(10) 2194-5. 

Tacrolimus, a macrolide derivative, has similar immunosuppressive properties to ciclosporin and has effects on T lymphocytes by inhibiting interleukin-2 production. On a weight basis, tacrolimus is about 100 times more potent than ciclosporin. In view of the outcome of several multicenter trials, it has been used as an alternative to ciclosporin as a baseline regimen for the prophylaxis of renal and liver transplant rejection and in the treatment of acute rejection (SED-13,1130) (SEDA-21, 390) (1). The clinical pharmacology, clinical use, and adverse effects profile of tacrolimus in organ transplantation have been extensively reviewed (2). 

Long-term follow-up (mean of 93 months) of tacroU-mus-based immunosuppression has been reported in 121 adult patients with liver transplants (10). Infections were the most common causes of deaths (17 patients out of 42), and half of them occurred during the first year after transplantation. Cardiovascular events (seven patients) or de novo malignancies (three patients) were also important causes of death. End-stage renal disease related to tacrolimus nephrotoxicity was noted in two patients who required renal transplantation At 7 years, other important adverse effects included hyperkalemia (30%) or... 

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